COMPOSITION:
DAVEDAX 2 mg. One tablet contains: active substance: Reboxetine 2 mg (as methanesulphonate). DAVEDAX 4 mg. One tablet contains: active substance: Reboxetine 4 mg (as methanesulphonate). Excipients: microcrystalline cellulose, calcium hydrogen phosphate dihydrate, crospovidone, silica dioxide, magnesium stearate.

PHARMACEUTICAL FORM AND PACKS:
2 mg tablets for oral administration. 4 mg tablets for oral administration. Box of 20 or 60 tablets in a blister pack.

PHARMACOTHERAPEUTIC CATEGORY:
Anti-depressant. ATC code N06A X 18

THERAPEUTIC INDICATIONS:
Reboxetine is indicated in the acute treatment of depression/major depression and for maintaining the clinical improvement in patients initially responding to treatment.

CONTRAINDICATIONS:
Known hypersensitivity to one of the components of the product. Reboxetine is contraindicated during pregnancy and lactation.

APPROPRIATE PRECAUTIONS FOR USE:
As Reboxetine has not been tested in patients with convulsive disorders in clinical studies and since rare cases of seizures have been reported in clinical studies, it should be given under close supervision to subjects with a history of convulsive disorders and it must be discontinued if the patient develops seizures. Concomitant use of monoamine oxidase inhibitors should be avoided in view of the potential risk (tyramine-like effect) owing to their mechanism of action. Concomitant use of Reboxetine with other antidepressants, (tricyclics, MAO inhibitors, SSRIs and lithium) has not been evaluated during clinical trials. As with all antidepressants, switches from depressive disorder to mania/hypomania have occurred during clinical trials. Close supervision of bipolar patients is, therefore, recommended. The risk of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close patient supervision during initial drug therapy is, therefore, recommended. Clinical experience with Reboxetine in patients affected by serious concomitant systemic diseases is limited. Close supervision should be applied in patients with current evidence of urinary retention, prostatic hypertrophy, glaucoma and a history of cardiac disease. At doses higher than the maximum recommended, orthostatic hypotension has been observed with greater frequency compared to its observation at the recommended doses. Particular attention should be paid when administering Reboxetine with other drugs known to lower blood pressure. Clinical experience with Reboxetine in the long-term treatment of elderly patients is, at present, limited. In this population, lowering of mean potassium levels was found starting from week 14; the magnitude of this reduction did not exceed 0.8 mmol/l and potassium levels never dropped below normal limits.

DRUG INTERACTIONS AND OTHER FORMS OF INTERACTION:
In vitro studies on metabolism indicate that Reboxetine is metabolised primarily by the isoenzyme CYP3A4 of cytochrome P450; Reboxetine is not metabolised by CYP2D6. It is therefore to be expected that the potent inhibitors of CYP3A4 (ketoconazole, nefazodone, erythromycin and fluvoxamine) increase the plasma concentrations of Reboxetine. In one study in the healthy volunteer, it was found that ketoconazole, a potent inhibitor of CYP3A4, increased the plasma concentrations of the enantiomers of Reboxetine by about 50%. Because of Reboxetine's narrow therapeutic margin, inhibition of its elimination is one of the major concerns. Reboxetine should not therefore be administered in combination with drugs that are known to inhibit CYP3A4, such as the azole antifungal agents, macrolide antibiotics, like erythromycin or fluvoxamine. In vitro studies have shown that Reboxetine does not inhibit the activity of the following isoenzymes of P450: CYP1A2, CYP2C9, CYP2C19 and CYP2E1. With the compounds metabolised by these enzymes there should be no pharmacokinetic interactions. At concentrations higher than those used in the clinical studies, Reboxetine inhibits CYP2D6 and CYP3A3, however, the results of in vivo studies suggest that they are improbable interactions with other drugs metabolised by these enzymes. The have been no significant pharmacokinetic interactions between Reboxetine and lorazepam. During their co-administration in healthy volunteers, mild to moderate drowsiness has been observed as well as an increased heart rate for a brief period, in the orthostatic position. Reboxetine in the healthy volunteer does not appear to potentiate the effect of alcohol on cognitive functions. The concomitant use of MAO inhibitors should be avoided owing to the potential risk (tyramine-like effect) due to their mechanism of action. The concomitant use of other antidepressants (tricyclics, MAO inhibitors, SSRIs and lithium) has not been evaluated during clinical trials. Concomitant use of ergot derivatives might result in increased blood pressure. Food intake delays the absorption of Reboxetine without, however, influencing the extent of absorption. Although data is not available from clinical studies, the possibility of hypokalaemia with concomitant use of potassium sparing diuretics should be considered.

SPECIAL WARNINGS:
Effects on the ability to drive and operate machinery
Reboxetine has no sedative action per se. No cognitive or psychomotor impairment has been observed with Reboxetine in clinical studies, also when the drug was co-administered with alcohol. However, as with all psychoactive drugs, patients should be cautioned about operating machinery and driving.

Use during pregnancy and lactation
Pregnancy
In humans experience is very limited. Therefore administration during pregnancy should be avoided.
Women of child-bearing age
If conception occurs during therapy, treatment is to be discontinued as soon as pregnancy is confirmed to limit foetal exposure to the drug.
Lactation
No information is available on the excretion of the drug into human breast milk. Therefore, Reboxetine should not be administered to breast-feeding women.

Keep out of the reach of children

DOSAGE, METHOD AND ROUTE OF ADMINISTRATION:
Davedax tablets are for oral administration.

Adults
The recommended therapeutic dose is 4 mg b.i.d. (8 mg/day) administered orally. Treatment can be initiated with the recommended dose. If after 3-4 weeks clinical response is incomplete, the administered dose can be increased to 10 mg/day. The maximum daily dose should not exceed 12 mg. The minimum effective dose has not yet been established.
Elderly patients
In clinical studies conducted in the elderly, Reboxetine was administered at a dose of 2 mg b.i.d. However, safety and efficacy were not assessed against a placebo. Consequently, as with all antidepressants not assessed in placebo controlled studies, the use of Reboxetine cannot be recommended.
Children
Administration to children is not recommended as safety and efficacy have not been assessed in this population.
Patients with renal or hepatic impairment
The initial dose in patients with renal or hepatic impairment should be 2 mg b.i.d. This dose can be increased depending on patient tolerability.

ACTION TO BE TAKEN IN CASE OF EXCESSIVE DOSE:

The acute toxicity studies carried out in animals indicates very low toxicity with a wide tolerability margin with respect to the pharmacologically active doses. Clinical signs and cause of death were related to the Central Nervous System (especially convulsive symptoms). In rare cases during clinical studies, doses higher than those recommended (12 to 20 mg/day) were administered to patients for periods ranging from a few days to a few weeks: the complaints reported included postural hypotension, anxiety and hypertension. The elderly might be particularly vulnerable to overdose. In pre-marketing clinical studies of the product, 5 cases of overdose were reported with Reboxetine alone or in combination with other drugs. The quantity of Reboxetine ingested alone was 52 mg in one patient and 20 mg in combination with other drugs in another patient. The remaining 3 patients had ingested an unknown quantity of Reboxetine. All 5 patients recovered fully. There was no report of any abnormal ECG, coma or convulsions following overdose of Reboxetine alone. In post-marketing experience, there were rare reports of cases of overdose in patients who had taken Reboxetine alone: none of these patients had a fatal outcome. Cases of non-fatal overdose have been reported in patients who had taken up to 240 mg of Reboxetine. One case of fatal overdose was reported in one patient who had ingested Reboxetine in combination with amitriptyline (at unknown doses). In case of overdose, cardiac function and vital signs should be monitored. General symptomatic supportive and/or emetic measures might be required.

UNDESIRABLE EFFECTS:

In clinical studies, Reboxetine was administered to over 2100 patients, of whom about 250 received the drug for at least 1 year. The common adverse effects requiring suspension of Reboxetine treatment with a frequency at least twice that of patients treated with a placebo included: insomnia, dizziness, dry mouth, nausea, sweats, sensation of incomplete bladder emptying (in males only), urinary hesitancy (in males only) and headache. The following information comes from short-term controlled studies. Very common or common adverse events which occurred with at least twice the frequency with Reboxetine compared to a placebo were:
[Very common (³ 1/10), Common (³ 1/100, < 1/10)]
Central nervous system disturbances
Very common: insomnia. Common: dizziness.
Visual disturbances
Common: focussing anomaly.
Cardiovascular disorders
Common~: tachycardia, palpitations, vasodilation, and orthostatic hypotension
Gastrointestinal disorders
Very common: dry mouth, constipation.
Common: absence or loss of appetite
Skin and subcutaneous disturbances
Very common: sweats
Urinary tract disturbances
Common: urinary hesitancy, sensation of incomplete bladder emptying, urinary infection
Disturbances of the male reproductive system
Common: erectile dysfunction, painful ejaculation, delayed ejaculation, testicular pain.
General disturbances
Common: chills

There have also been spontaneous reports of aggressiveness, cold extremities, nausea, vomiting, allergic dermatitis/rash. To assess the long-term tolerability of the drug, 143 adult patients were given Reboxetine and 140 a placebo in a controlled study. Adverse events were reported in 28% of patients treated with reboxetine and in 23% of patients treated with the placebo and in 4% and 1% of cases respectively these led to suspension of the treatment. Each event occurred with similar frequency with Reboxetine and the placebo. Among the rare adverse events reported in long-term treatment, no event other than those observed in the short term treatment was observed.

In short-term controlled studies in depressed patients, no clinically significant difference was observed between the two sexes in the frequency of symptoms deriving from the treatment, with the exception of urological type events (such as sensation of incomplete bladder emptying, urinary hesitancy and urinary frequency), a higher percentage of which were reported in male patients treated with Reboxetine (31.4% [143/456]) compared to female patients (7% [59/847]). On the other hand, the frequency of urological type events was similar between male patients (5% [15/302]) and female patients (8.4% [37/440]), treated with placebo. In the elderly, the absolute frequency of adverse events as well as single events never exceeded those reported above. Signs and symptoms reported "ex novo" after abrupt withdrawal of the treatment were rare and, in any case, less frequent in patients treated with Reboxetine, compared to those treated with placebo. In short term studies in depression, cardiac frequency, when assed by means of ECG, was moderately increased in patients treated with Reboxetine by 6-12 beats compared to the placebo group.

In all short term controlled studies in depression, the mean variation of cardiac frequency for patients treated with Reboxetine, was equivalent to 3.0-6.4 and 2.9 beats per minute respectively when standing and in the sitting and supine positions, compared to 0 – 0 and 0.5 beats in patients treated with the placebo in equivalent positions. In these same studies, 0.8% of patients treated with Reboxetine suspended ingestion of the drug due to tachycardia, compared to 0.1% of patients treated with placebo.

In case of onset of any undesirable effect not among those described above, experienced during treatment, the patient should inform his doctor or pharmacist.

IMPORTANT:
The expiry date indicated refers to the product in an unopened and correctly stored pack.
Do not use if the pack appears to be damaged.
Do not discard after use. Use the appropriate containers for the disposal of various medicinal products.